Our initial focus is on MCD, a syndrome in which infected B cells are in the lytic phase of the viral replication cycle. Infected cells express several KSHV structural glycoproteins at the surface, including gH/gL, gB, and K8.1A. Though a relatively rare disease, MCD incidence continues to rise despite antiretroviral therapy and the associated improvements in immune function. MCD if a life-threatening disease (median life expectancy <3 years after diagnosis), and no standards for clinical management have been developed. Hence immunotoxins to selectively kill infected B cells may prove beneficial. We previously reported the design and characterization of an immunotoxin, YC15-PE38, that potently killed a gH transfectant cell line and strongly inhibited infectious virus production from Vero-219 cells harboring an episomal infectious KSHV genome with EGFP and RFP that serve as reporters for latent and lytic infection, respectively. We have now characterized a new immunotoxin, 2014-PE38, against a the KSHV glycoprotein K8.1A, which is expressed earlier than gH as cells enter the lytic phase of replication. This immunotoxin potently inhibits infectious virus production from Vero-219 cells;control experiments verified the specificity of this effect based on targeting K8.1A surface antigen, and confirmed that the inhibitory effects were due to selective killing of the virus-producing cells. In combination drug treatment experiments, the immunotoxin complemented the activity of ganciclovir. Assays have been extended to other cell types that are more biologically relevant, incuding the iSLK#10, an endothelial cell line that harbors a reporter-carrying KSHV genome inducible by doxycicline, and BCBL cells derived from a primary infusion lymphoma in which KSHV lytic expression can be experimentally induced. Preliminary results indicate activity of the 2014-PE38 immunotoxin, though the effects are less dramatic than with Vero-219 cells. Additional experiments are underway to assess whether these distinctions reflect true biological differences between the different infected cell types, or simply experimental intiricacies that must be resolved.